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The Role of the Y Chromosome in Cancer


Bladder cancer is a sexually dimorphic disease, with men having a threefold higher incidence than women. Interestingly, loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers, but its clinical and biological significance was recently unknown in any cancer type. Using genomic and transcriptomic studies, we recently reported that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells, as well as those with targeted deletion of the Y chromosome by CRISPR-Cas9. Y-positive (Y+) and Y-negative (Y-) tumors grew similarly in vitro, whereas Y- tumors were more aggressive than Y+ tumors in immune-competent hosts in a T cell-dependent manner. Flow cytometric analyses demonstrated that Y- tumors promote exhaustion of CD8+ T cells in the tumor microenvironment. Importantly, from a translational therapeutic point of view, compared with Y+ tumors, Y- tumors exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. With bladder cancer as a clinically relevant model to study LOY, we are now using pioneering reagents and approaches we developed to fully understand how the Y chromosome regulates cell biology in normal and malignant settings.

Enhancing Cancer Immunotherapy


For the past 40 years, one of the most effective immunotherapies in any malignancy has been the intravesical instillation of bacillus Calmette-Guerin (BCG) for bladder cancer. BCG is an attenuated tuberculoid strain of bacteria that has become part of the standard of care for patients with bladder cancer. Over the past five years, immune checkpoint inhibitors that target the PD-1–PD-L1 axis have been approved for use in bladder cancer, representing the first major therapeutic change in decades. However, although a small fraction of patients show durable therapeutic responses or are cured, the vast majority (over 75 percent) remain unresponsive, highlighting an urgent need to better understand and improve these therapies. The Theodorescu Lab has developed several novel models of murine bladder cancer and is using them to develop approaches that enhance the efficacy of checkpoint inhibitors. Most recently, the lab used an in vivo functional genomic depletion screen and pharmacologic approaches to identify DDR2 as a leading target for the enhancement of the response to anti–PD-1 immunotherapy. Current work in the Theodorescu Laboratory aims to identify other molecules like DDR2 that, when inhibited, will enhance checkpoint inhibitor efficacy, while also collaborating with clinical investigators to design clinical trials of combination targeting of DDR2 and PD-1.

Computational and Single Cell Approaches to Precision Cancer Medicine


One factor driving the Theodorescu Lab’s interest in bladder cancer research is the striking lack of therapeutic options for these patients, especially those with advanced disease, where prognosis is poor (pancreas, brain tumors, liver tumors, etc.). In addition, part of the difficulty in treating cancer is the high degree of genetic heterogeneity and variable gene expression programs among different bladder tumors and cells within the same tumor. The Theodorescu Lab has developed three approaches to help address these issues:

The first approach has been to combine single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. Our studies have described a cancer cell population predictive of the response to major bladder cancer therapeutics, such as immunotherapy and chemotherapy, populations that would have been missed by conventional bulk tumor sequencing. Importantly, this data and approach, if applied in other settings, also provides a compelling framework for designing biomarker-guided.

The second approach has been to develop and test a platform called “the Molecular Twin” that combines data from multiple clinical and molecular analytes from both the tumor and host, including DNA, RNA, lipid and protein from patients with pancreatic cancer, with computational pathology. Artificial Intelligence (AI) and machine learning approaches were then applied to this data to identify which specific set of multi-omic biomarker panels are highly predictive of disease survival outcome. As this comprehensive analytic approach increased the cost and resource requirements of multi-omic AI precision medicine, we applied a recursive feature elimination strategy to our full multi-omic dataset. This strategy removed, at each step, the least informative features while maintaining predictive performance in search of an optimal balance between analytic burden and predictive performance. Doing so would simultaneously reduce the resource requirements, cost and time constraints inherent to current comprehensive molecular testing. This approach has substantial potential to reduce global disparities in cancer care and improve patient outcomes.

The third approach has been COXEN (CO-eXpression ExtrapolatioN), a means of extrapolating therapeutic research on other cancer types to bladder cancer, effectively examining individual molecular targets expressed in bladder tumors and comparing their expression profile to other patients with different tumor types containing similar molecular target profiles for which therapeutic response is known. A national SWOG/NCI clinical trial evaluating the ability of COXEN to predict therapy response in bladder cancer constitutes one of the first precision medicine trials in bladder cancer.

Discovery of Tumor and Metastasis Suppressor Genes


Early work in the Theodorescu Laboratory led to the discovery of the first metastasis suppressor, RhoGDI2, using a novel approach that combined gene expression profiling of cell line data with that of clinical tumors. This work was among the first to demonstrate the utility of this approach in finding both mechanistically and clinically relevant genes and has been subsequently used by others. Recently, the Theodorescu Lab used in vivo functional genomic screening to identify several other suppressors of cancer growth, including glycogen debranching enzyme (AGL), which had no previously known role in cancer. Mechanistic studies of RhoGDI2 and AGL have revealed that these genes drive aggressive tumor behavior via convergent pathways, influencing the formulation of new therapeutic approaches targeting endothelin receptor and CD44 in bladder cancer. Clinical trials are being planned for bladder cancer patients at high risk of metastasis development, constituting a prototypical example of the translation of bench-to-bedside research and precision oncology. Mechanistic work on defining how these genes work continues.

Drug Discovery


Dan Theodorescu, MD, PhD, initiated the study of the Ras family of GTPases in bladder cancer during his graduate work, a focus that the current work in the Theodorescu Laboratory continues. The lab has identified the Ral GTPase, a downstream effector of Ras, as a significant driver of bladder cancer through a novel mechanism involving CD24 and the androgen receptor. This discovery unveils a first-time understanding of how the androgen receptor mediates bladder cancer growth and progression. Since U.S. Food and Drug Administration–approved therapies target the androgen receptor, this work has established the concept of treating bladder tumors with high CD24 expression using androgen receptor blockers. As Ral also promotes tumor growth via AR/CD24-independent mechanisms, the Theodorescu Lab has developed agents for Ral inhibition. By targeting the inactive form of Ral through an allosteric site, instead of the common approach of targeting the active site of GTPases, the lab utilized computational drug-docking algorithms to discover the first targeted agent against Ral GTPase. This agent is now in development for precision medicine clinical trials by a pharmaceutical collaborator, and the Theodorescu Lab is actively working on optimizing drug combinations for use with Ral inhibitors.

Contact the Theodorescu Lab

8700 Beverly Blvd.
Davis Building, Room 3057
Los Angeles, CA 90048